1. Field of Invention
The present invention relates to the field of simultaneous transdermal delivery of Doxylamine or its various salts and Pyridoxine or its various salts and active metabolites from Novel pharmaceutical compositions. The pharmaceutical compositions have simultaneous in vitro release profile of Doxylamine and Pyridoxine from 1-3 days and 1-7 days. In particular, the pharmaceutical compositions of the present invention includes liquid formulations, semisolid formulations, and polymer matrix formulations comprised of Doxylamine, Pyridoxine and a vehicle system. Surprisingly, from a liquid formulation the average in vitro flux for Doxylamine Succinate and Pyridoxine Hydrochloride is almost the same for any period from 24 to 168 hours. Furthermore, surprisingly, from semisolid formulations the average in vivo flux over seven days is the same for Doxylamine Succinate and Pyridoxine Hydrochloride.
2. Description of Related Art
Nausea and Vomiting during Pregnancy (NVP) occurs in approximately 70% of pregnant women, making it the most common ailment during pregnancy1. Severity and occurrence of NVP symptoms are variable among women. Severity of symptoms like gagging, nausea, vomiting, retching can vary from mild to severe. A spectrum of symptoms occur from morning throughout the day and even into the night. Generally symptoms of NVP onset between 4-9 weeks, get severe between 7-12 weeks and then tapers down from the 12th week. However, 15% of pregnant women experience NVP symptoms for up to 20 weeks, and less than 10% experience it throughout their pregnancy4,2. NVP affects women's quality and comfort of life during pregnancy2. A study was conducted with 160 pregnant women and reported that 74% women had nausea, of which 80% reported nausea all day long3. The initial approach in managing NVP is to make dietary changes including the avoidance of trigger odors and foods. If that approach does not resolve symptoms on its own, guidance recommends the addition of pharmacotherapy5.
DICLEGIS® is the only US FDA approved drug for the treatment of NVP. It is a delayed release oral tablet, a fixed dose combination of 10 mg Doxylamine Succinate and 10 mg Pyridoxine Hydrochloride6.
A number of shortcomings are associated with the commercially available oral tablet DICLEGIS both in dosage regimen and pharmacokinetic profile. The first challenge is the dose regimen as stated in FDA DICLEGIS label to “take two tablets daily at bedtime and if symptoms are not adequately controlled, the dose can be increased to a maximum recommended dose of four tablets daily (one in the morning, one mid-afternoon and two at bedtime)”6. This multiple dose regimen is inconvenient for pregnant women, particularly for those who experience vomiting within a short time after dosing (i.e., within one hour) and have uncertainty as to whether taking another dose would be permissible. The second challenge is taking the dose on an empty stomach because the absorption of Doxylamine Succinate and Pyridoxine Hydrochloride gets delayed when administered with food. Moreover, it is reported that the bioavailability of pyridoxine reduces with food6. Hence forth for treatment of NVP, there is a need for an improved drug delivery system which can reduce dosing frequency of Doxylamine and Pyridoxine, and provide a sustained release for a prolonged therapeutic effect overcoming the problems associated with the administration of delayed release DICLEGIS tablet.
Transdermal drug delivery is a delivery of drug through, for example, an intact skin surface. By topical application of transdermal composition or transdermal delivery system to the skin surface, such as intact skin, drug is continuously delivered from a transdermal delivery system through the skin (via transcellular, intercellular and transappendageal routes) to achieve a systemic effect.
Transdermal delivery of Doxylamine Succinate and Pyridoxine Hydrochloride can address the challenges associated with the commercially available oral tablet (DICLEGIS) including dosage regimen and pharmacokinetic profile. With respect to dosage regimen, the dosing frequency can be reduced and simplified by applying a pharmaceutical composition or transdermal delivery system to, for example, intact skin which can provide continuous or sustained systemic delivery of Doxylamine Succinate and Pyridoxine Hydrochloride throughout the duration of application. By transdermal delivery, Doxylamine Succinate and Pyridoxine Hydrochloride reaches systemic circulation through the skin. Thus, absorption of both drugs is not affected by a fed or fasted state, unlike an oral tablet which should be taken on an empty stomach. Depending upon the severity of symptoms, the duration of topical application or transdermal delivery of the drugs can be once a day, once every two days, once every three days, once every four days, once every five days, once every six days, once in a week, or possibly even once every 15 days. Therefore transdermal delivery of Doxylamine Succinate and Pyridoxine Hydrochloride can improve the quality of life of those suffering from nausea and vomiting with a simplified and convenient therapeutic regimen.
There are patents known in the art for oral delivery of Doxylamine Succinate and Pyridoxine Hydrochloride. For example, U.S. Pat. No. 6,340,695B1 discloses an enterically coated rapid onset oral formulation comprising Doxylamine Succinate and Pyridoxine Hydrochloride. US Patent Application Number 20140335176A1 discloses a disintegrant free delayed release oral composition of Doxylamine Succinate and Pyridoxine Hydrochloride. U.S. Pat. No. 9,089,489B2 discloses and states that “a dual release oral dosage system comprising immediate release component and delayed release component”. The prior art does not describe or inform on Transdermal Delivery of Doxylamine Succinate and Pyridoxine Hydrochloride, nor does it inform on techniques which can reduce the dosing frequency to at least once in three days, to at least once in seven days.
The invention provides a transdermal pharmaceutical composition in a liquid formulation comprising: Doxylamine as a free base or any of its salts; Pyridoxine as a free base or any of its salts or its active metabolites; and a vehicle system wherein the vehicle system comprises excipients selected from the group consisting of solvents, enhancers, pH adjusting agents, and combinations thereof.
The invention provides a transdermal pharmaceutical composition wherein: Doxylamine is present in an amount selected from the group consisting of between 0.5-49 wt %, between 2-30 wt %, between 5-20 wt %; Pyridoxine is present in an amount selected from the group consisting of between 0.5-49 wt %, between 2-30 wt %, between 5-20 wt %, and wherein the vehicle system is present in an amount selected from the group consisting of between 2-99 wt %, preferably between 40-96 wt %, and between 60-90 wt %.
The invention provides a method of treating and/or preventing nausea or nausea and vomiting in a patient comprising: selecting a patient in need of treating and/or preventing nausea or nausea and vomiting; administering to the patient the transdermal pharmaceutical composition, wherein nausea or nausea and vomiting is treated and/or prevented in the patient.
The invention provides a method, wherein the application is to skin, such as intact skin, and wherein frequency of topical application is selected from the group consisting of once in a day, once in two days, once in three days, once in four days, once in five days, once in six days, days, once in a week, once in ten days, and once in fifteen days.
The invention provides a method of treating and/or preventing nausea and vomiting in pregnancy (NVP) in a patient comprising: selecting a patient in need of treating and/or preventing NVP; administering to the patient the transdermal pharmaceutical composition wherein NVP is treated and/or prevented in the patient.
The invention provides a method wherein the application is to intact skin and wherein frequency of topical application is selected from the group consisting of once in a day, once in two days, once in three days, once in four days, once in five days, once in six days, once in a week, once in ten days, and once in fifteen days.
The invention provides a transdermal pharmaceutical composition in a liquid formulation comprising: Doxylamine as a free base or any of its salts; and a vehicle system wherein the vehicle system comprises excipients selected from the group consisting of solvents, enhancers, pH adjusting agents, and combinations thereof.
The invention provides a transdermal pharmaceutical composition wherein: Doxylamine is present in an amount selected from the group consisting of between 0.5-80 wt %, between 2-30 wt %, between 5-20 wt %, and wherein the vehicle system is present in an amount selected from the group consisting of between 20-99.5 wt %, between 70-98 wt %, and between 80-95 wt %.
The invention provides a method of treating and/or preventing nausea or nausea and vomiting in a patient comprising: selecting a patient in need of treating and/or preventing nausea or nausea and vomiting; administering to the patient the transdermal pharmaceutical composition, wherein nausea or nausea and vomiting is treated and/or prevented in the patient.
The invention provides a method wherein the application is to intact skin and wherein frequency of topical application is selected from the group consisting of once in a day, once in two days, once in three days, once in four days, once in five days, once in six days, once in a week, once in ten days, and once in fifteen days.
The invention provides a method of treating and/or preventing nausea and vomiting in pregnancy (NVP) in a patient comprising: selecting a patient in need of treating and/or preventing NVP; administering to the patient the transdermal pharmaceutical composition wherein NVP is treated and/or prevented in the patient.
The invention provides a method wherein the application is to intact skin and wherein frequency of topical application is selected from the group consisting of once in a day, once in two days, once in three days, once in four days, once in five days, once in six days, once in a week, once in ten days, and once in fifteen days.
The invention provides a transdermal pharmaceutical composition in a liquid formulation comprising: pyridoxine as a free base or any of its salts or its active metabolites; and a vehicle system wherein the vehicle system comprises excipients selected from the group consisting of solvents, enhancers, pH adjusting agents, and combinations thereof.
The invention provides a transdermal pharmaceutical composition wherein: Pyridoxine is present in an amount selected from the group consisting of between 0.5-80 wt %, between 2-30 wt %, and between 5-20 wt %, wherein the vehicle system is present in an amount selected from the group consisting of between 20-99.5 wt %, between 70-98 wt %, and between 80-95 wt %.
The invention provides a method of treating and/or preventing nausea or nausea and vomiting in a patient comprising: selecting a patient in need of treating and/or preventing nausea or nausea and vomiting; administering to the patient the transdermal pharmaceutical composition, wherein nausea or nausea and vomiting is treated and/or prevented in the patient.
The invention provides a method wherein the application is to intact skin and wherein frequency of topical application is selected from the group consisting of once in a day, once in two days, once in three days, once in four days, once in five days, once in six days, once in a week, once in ten days, and once in fifteen days.
The invention provides a method of treating and/or preventing nausea and vomiting in pregnancy (NVP) in a patient comprising: selecting a patient in need of treating and/or preventing NVP; administering to the patient the transdermal pharmaceutical composition, wherein NVP is treated and/or prevented in the patient. The invention provides a method wherein the application is to intact skin and wherein frequency of topical application is selected from the group consisting of once in a day, once in two days, once in three days, once in four days, once in five days, once in six days, once in a week, once in ten days, and once in fifteen days.
The invention provides a transdermal pharmaceutical composition in a semisolid formulation comprising: Doxylamine as a free base or any of its salts; Pyridoxine as a free base or any of its salts or its active metabolites; and a vehicle system wherein the vehicle system comprises excipients selected from the group consisting of solvents, enhancers, polymers or gelling agents or thickening agents, pH adjusting agents, and combinations thereof. The invention provides a transdermal pharmaceutical composition wherein: Doxylamine is present in an amount selected from the group consisting of between 0.5-49 wt %, between 2-30 wt %, and between 5-20 wt %; Pyridoxine is present in an amount selected from the group consisting of between 0.5-49 wt %, between 2-30 wt %, and between 5-20 wt %; and wherein the vehicle system is present in an amount selected from the group consisting of between 2-99 wt %, between 40-96 wt %, and between 60-90 wt %.
The invention provides a method of treating and/or preventing nausea or nausea and vomiting in a patient comprising: selecting a patient in need of treating and/or preventing nausea or nausea and vomiting; administering to the patient the transdermal pharmaceutical composition, wherein nausea or nausea and vomiting is treated and/or prevented in the patient.
The invention provides a method, wherein the application is to intact skin and wherein frequency of topical application is selected from the group consisting of once in a day, once in two days, once in three days, once in four days, once in five days, once in six days, once in a week, once in ten days, and once in fifteen days.
The invention provides a method of treating and/or preventing nausea and vomiting in pregnancy (NVP) in a patient comprising: selecting a patient in need of treating and/or preventing NVP; administering to the patient the transdermal pharmaceutical composition, wherein NVP is treated and/or prevented in the patient. The invention provides a method wherein the application is to intact skin and wherein frequency of topical application is selected from the group consisting of once in a day, once in two days, once in three days, once in four days, once in five days, once in six days, once in a week, once in ten days, and once in fifteen days.
The invention provides a transdermal pharmaceutical composition as a semisolid formulation comprising: Doxylamine as a free base or any of its salts; and a vehicle system wherein the vehicle system comprises excipients selected from the group consisting of solvents, enhancers, polymers or gelling agents or thickening agents, pH adjusting agents, and combinations thereof. The invention provides a transdermal pharmaceutical composition wherein: Doxylamine is present in an amount selected from the group consisting of between 0.5-80 wt %, between 2-30 wt %, and between 5-20 wt %; and wherein the vehicle system is present in an amount selected from the group consisting of between 20-99.5 wt %, between 70-98 wt %, and between 80-95 wt %.
The invention provides a method of treating and/or preventing nausea or nausea and vomiting in a patient comprising: selecting a patient in need of treating and/or preventing nausea or nausea and vomiting; administering to the patient the transdermal pharmaceutical composition, wherein nausea or nausea and vomiting is treated and/or prevented in the patient.
The invention provides a method wherein the application is to intact skin and wherein frequency of topical application is selected from the group consisting of once in a day, once in two days, once in three days, once in four days, once in five days, once in six days, once in a week, once in ten days, and once in fifteen days. The invention provides a method of treating and/or preventing nausea and vomiting in pregnancy (NVP) in a patient comprising: selecting a patient in need of treating and/or preventing NVP; administering to the patient the transdermal pharmaceutical composition, wherein NVP is treated and/or prevented in the patient. The invention provides a method wherein the application is to intact skin and wherein frequency of topical application is selected from the group consisting of once in a day, once in two days, once in three days, once in four days, once in five days, once in six days, once in a week, once in ten days, and once in fifteen days.
The invention provides a transdermal pharmaceutical composition in a semisolid formulation comprising: Pyridoxine as a free base or any of its salts or its active metabolites; and a vehicle system wherein the vehicle system comprises excipients selected from the group consisting of solvents, enhancers, polymers or gelling agents or thickening agents, pH adjusting agents, and combinations thereof.
The invention provides a transdermal pharmaceutical composition wherein: Pyridoxine is present in an amount selected from the group consisting of between 0.5-80 wt %, between 2-30 wt %, and between 5-20 wt %; and wherein the vehicle system is present in an amount selected from the group consisting of between 20-99.5 wt %, between 70-98 wt %, and between 80-95 wt %.
The invention provides a method of treating and/or preventing nausea or nausea and vomiting in a patient comprising: selecting a patient in need of treating and/or preventing nausea or nausea and vomiting; administering to the patient the transdermal pharmaceutical composition, wherein nausea or nausea and vomiting is treated and/or prevented in the patient. The invention provides a method wherein the application is to intact skin and wherein frequency of topical application is selected from the group consisting of once in a day, once in two days, once in three days, once in four days, once in five days, once in six days, once in a week, once in ten days, and once in fifteen days.
The invention provides a method of treating and/or preventing nausea and vomiting in pregnancy (NVP) in a patient comprising: selecting a patient in need of treating and/or preventing NVP; administering to the patient the transdermal pharmaceutical composition, wherein NVP is treated and/or prevented in the patient. The invention provides a method wherein the application is to intact skin and wherein frequency of topical application is selected from the group consisting of once in a day, once in two days, once in three days, once in four days, once in five days, once in six days, once in a week, once in ten days, and once in fifteen days.
The invention provides a transdermal pharmaceutical composition in a polymer matrix comprising: Doxylamine as a free base or any of its salts; Pyridoxine as a free base or any of its salts or its active metabolites; and a vehicle system wherein the vehicle system comprises excipients selected from the group consisting of solvents, enhancers, plasticizers, polymers, pH adjusting agents, and combinations thereof. The invention provides a transdermal pharmaceutical composition wherein: Doxylamine is present in an amount selected from the group consisting of between 0.5-49 wt %, between 2-30 wt %, and between 5-20 wt %; Pyridoxine is present in an amount selected from the group consisting of between 0.5-49 wt %, between 2-30 wt %, and between 5-20 wt %; and wherein the vehicle system is present in an amount selected from the group consisting of between 2-99 wt %, between 40-96 wt %, and between 60-90 wt %.
The invention provides a method of treating and/or preventing nausea or nausea and vomiting in a patient comprising: selecting a patient in need of treating and/or preventing nausea or nausea and vomiting; administering to the patient the transdermal pharmaceutical composition wherein nausea or nausea and vomiting is treated and/or prevented in the patient. The invention provides a method wherein the application is to intact skin and wherein frequency of topical application is selected from the group consisting of once in a day, once in two days, once in three days, once in four days, once in five days, once in six days, once in a week, once in ten days, and once in fifteen days.
The invention provides a method of treating and/or preventing nausea and vomiting in pregnancy (NVP) in a patient comprising: selecting a patient in need of treating and/or preventing NVP; administering to the patient the transdermal pharmaceutical composition wherein NVP is treated and/or prevented in the patient. The invention provides a method wherein the application is to intact skin and wherein frequency of topical application is selected from the group consisting of once in a day, once in two days, once in three days, once in four days, once in five days, once in six days, once in a week, once in ten days, and once in fifteen days.
The invention provides a transdermal pharmaceutical composition in a polymer matrix comprising: Doxylamine as a free base or any of its salts; and a vehicle system wherein the vehicle system comprises excipients selected from the group consisting of solvents, enhancers, plasticizers, polymers, pH adjusting agents, and combinations thereof. The invention provides a transdermal pharmaceutical composition wherein: Doxylamine is present in an amount selected from the group consisting of between 0.5-80 wt %, between 2-30 wt %, and between 5-20 wt %; and wherein the vehicle system is present in an amount selected from the group consisting of between 20-99.5 wt %, between 70-98 wt %, and between 80-95 wt %.
The invention provides a method of treating and/or preventing nausea or nausea and vomiting in a patient comprising: selecting a patient in need of treating and/or preventing nausea or nausea and vomiting; administering to the patient the transdermal pharmaceutical composition wherein nausea or nausea and vomiting is treated and/or prevented in the patient.
The invention provides a method wherein the application is to intact skin and wherein frequency of topical application is selected from the group consisting of once in a day, once in two days, once in three days, once in four days, once in five days, once in six days, once in a week, once in ten days, and once in fifteen days.
The invention provides a method of treating and/or preventing nausea and vomiting in pregnancy (NVP) in a patient comprising: selecting a patient in need of treating and/or preventing NVP; administering to the patient the transdermal pharmaceutical composition wherein NVP is treated and/or prevented in the patient. The invention provides a method wherein the application is to intact skin and wherein frequency of topical application is selected from the group consisting of once in a day, once in two days, once in three days, once in four days, once in five days, once in six days, once in a week, once in ten days, and once in fifteen days.
The invention provides a transdermal pharmaceutical composition in a polymer matrix comprising: Pyridoxine as a free base or any of its salts or its active metabolites; and a vehicle system wherein the vehicle system comprises excipients selected from the group consisting of solvents, enhancers, plasticizers, polymers, pH adjusting agents, and combinations thereof. The invention provides a transdermal pharmaceutical composition wherein: Pyridoxine is present in an amount selected from the group consisting of between 0.5-80 wt %, between 2-30 wt %, and between 5-20 wt %; and wherein the vehicle system is present in an amount selected from the group consisting of between 20-99.5 wt %, between 70-98 wt %, and between 80-95 wt %.
The invention provides a method of treating and/or preventing nausea or nausea and vomiting in a patient comprising: selecting a patient in need of treating and/or preventing nausea or nausea and vomiting; administering to the patient the transdermal pharmaceutical composition wherein nausea or nausea and vomiting is treated and/or prevented in the patient. The invention provides a method wherein the application is to intact skin and wherein frequency of topical application is selected from the group consisting of once in a day, once in two days, once in three days, once in four days, once in five days, once in six days, once in a week, once in ten days, and once in fifteen days.
The invention provides a method of treating and/or preventing nausea and vomiting in pregnancy (NVP) in a patient comprising: selecting a patient in need of treating and/or preventing NVP; administering to the patient the transdermal pharmaceutical composition wherein NVP is treated and/or prevented in the patient. The invention provides a method wherein the application is to intact skin and wherein frequency of topical application is selected from the group consisting of once in a day, once in two days, once in three days, once in four days, once in five days, once in six days, once in a week, once in ten days, and once in fifteen days.
The invention provides doxylamine and/or pyridoxine for use in the preparation of a medicament for use in treating and/or preventing nausea and vomiting in pregnancy (NVP). The invention provides doxylamine and/or pyridoxine for use in the preparation of a medicament for use in treating and/or preventing nausea and vomiting.
The invention provides method for treating or preventing a disease or condition in a patient, wherein the disease or condition is selected from the group consisting of nausea and vomiting or NVP, and combinations thereof, wherein said method comprises: selecting a patient in need of treating or preventing said disease or condition; administering to the patient the composition of the invention in a therapeutically effective amount, thereby treating and/or preventing the condition.
All references cited herein are incorporated herein by reference in their entireties.